Clinical Science (2010) 119, 97-109 - B. Langhans and others

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Clinical Science (2010) 119, (97–109) (Printed in Great Britain)

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Core-specific adaptive regulatory T-cells in different outcomes of hepatitis C

Bettina Langhans^*, Ingrid Braunschweiger^*, Simone Arndt^*, Wibke Schulte^*, Judith Satoguina^†, Laura E. Layland^†‡, Natascha Vidovic^§, Achim Hoerauf^†, Johannes Oldenburg^§, Tilman Sauerbruch^* and Ulrich Spengler^*

*Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany, †Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany, ‡Institute of Medical Microbiology, Immunology and Hygiene, TUM, Trogerstr. 30, 81675 München, Germany, and §Institute for Experimental Hematology and Transfusion Medicine, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany

Key words: adaptive regulatory T-cell (T_reg-cell), cytokine release, hepatitis C virus (HCV), immunosuppression, T-cell cloning.

Abbreviations: APC, antigen-presenting cell; CMV, cytomegalovirus; CTLA-4, cytotoxic T-lymphocyte antigen-4; Foxp3, forkhead transcription factor box 3; GARP, glycoprotein A repetitions predominant; GITR, glucocorticoid-inducible tumour necrosis factor receptor; HCV, hepatitis C virus; IFN-γ, interferon-γ; IL, interleukin; int, intermediate; MFI, mean fluorescence intensity; PBMC, peripheral blood mononuclear cell; PD1, programmed death 1; PE, phycoerythrin; PHA, phytohaemagglutinin; rIL-2, recombinant IL-2; SI, stimulation index; TGF, transforming growth factor; Th, T-helper; T_reg-cell, regulatory T-cell.

Correspondence: Dr Bettina Langhans (email bettina.langhans@ukb.uni-bonn.de).

CD4⁺ T_reg-cells (regulatory T-cells) probably contribute to the impaired virus-specific T-cell responses in chronic HCV (hepatitis C virus) infection; however, their antigen-specificity has remained elusive. In the present study, we analysed peripheral blood CD4⁺ T_reg-cells in patients with chronic hepatitis C and subjects with self-limited HCV infection and characterized individual T_reg-cell clones obtained from both groups at the phenotypic and functional level. Foxp3 (forkhead box p3)⁺CD25⁺CD4⁺ T_reg-cells were detected more frequently in patients with chronic hepatitis C than self-limited HCV infection, which responded to HCV core stimulation and inhibited proliferation of reporter cells. Cloning under limiting dilution conditions resulted in 14 and six hypoproliferative Foxp3⁺CD25⁺CD127⁻CD4⁺ T-cell clones from patients with chronic hepatitis C and subjects with self-limited HCV infection respectively. All clones expressed T_reg-cell markers and produced IL (interleukin)-10 upon mitogen stimulation. However, exclusively T_reg-cell clones from chronic hepatitis C produced IL-10 in response to HCV core and inhibited proliferation of reporter T-cells. These core-specific T_reg-cell clones recognized epitopes in two regions of HCV core (amino acids 1–44 and 79–113). Co-culture inhibition assays demonstrated T_reg-cells to inhibit reporter T-cells via secretion of IL-10 and IL-35 rather than cell-contact-dependent mechanisms. Finally, the HCV-specific T_reg-cell clones lost their functional capacity, along with Foxp3 expression, if kept in culture without HCV core exposure. In conclusion, we identified functionally active HCV core-specific T_reg-cells in patients with chronic hepatitis C, which share their epitopes with conventional T-cells and require the continued presence of antigen to maintain their functional differentiation. Thus HCV core-specific T_reg-cells may contribute to the immunoregulatory balance in chronic hepatitis C.